Process of producing methylamines substituted in the methyl group by a cyclic radicle



Patented Aug. 23, 1932 err? 'WILHELM nnnznnne, IBEBLIN-WILMEBSDOBF, AND HANS Lanes, on BERLIN- FRIEDENAU, GERMANY, lassreivons TO naflraannivrnnusrnin I screens, on ,raenKronT-oN-Tnn-nmm, GERMANY rnocnss or rnonucnve mnrnynnivrrnns sunsrrr'nrnn IN THE METHYL enour BY A CYGLIC RADIGLE i No Drawing.

The present invention relates to a process of producingmethylamines of the formula RGH NH B being acarbocyclic radicle.

The invention is observations: v p 7 vVhenreacting on a carbocyclic compound with a halogenomethylphthalimide (compare Gabriel, Berichte der Deutschen Chem ischen Gesellschaft, vol. 41, page 2 12) there is obtained smoothly a nucleal synthesis which may be supposed to occur for example in accordance with the following equation: I

oo 'oo O 5H =aryL OHZI N 7 oo \00 v This synthesis may be carried out in the presence of a solvent and alsoa' catalyst may be present.

When theproduct of this condensation is treated with a cold alkali metal hydroxide solution it is converted into the corresponding salt of a substituted alkylate'd phthala mic acid, probably in accordance, for example with the equation: 1

ary1.CHz.NH.CO

V coon aryLCHaNHaHOl-I-Cfliy r Y ooon Thus the new process of the manufacture of derivatives of methylamines consists in treating a carbocyclic compound with a halogenomethylphthalimide and decomposing the condensation product by successive treatment with an alkali and an acid.

based on the following Application filed March 23,' 1e2e; "Serial No. 96,870;

The following examples illustrate our invention Withoutlimiting it,.the parts being by weight:

in a reflux'apparatus until evolution of by; drogen chloride ,has ceased. The benzene is then expelled and the residue crystallized parts of caustic soda solution of 35 percent AKTIENGESELL- parts of chloromethylphthalimidei are boiled with 500 parts of pure benzene and 10 parts of zinc chloride for several hours strength, 500 parts of water and 500 partsoi'" alcohol l until dissolution is complete then 280 parts of hydrochloric acid of 25 per cent strength areadded, the alcohol is expelled and the mass stirred While hot until a clean solution is obtained.- On cooling p thalic acid separates and, aftertheremoval of this ac1d,the solution is made alkallne' WltllCdllStlC there are introduced. 195 parts of chloromethylphthalimide and 10 parts of zincchlo ride and the whole is heated at to C.

for some hours, While stirring, untilzevolu tion of hydrogen chloride ceases. The unal-Y tered di'methylbenzene is now expelled with steam and the residue is crystallized from hot alcohol whereby, in addition to a small proportion of a substance sparingly soluble in a1 cohol, 2. Ldimethylbenzylphthalimide (pseue documylphthalimide') having a melting point 1 of 111 0., is obtained. parts of this com pound are stirred in the cold with 124 parts of caustic" soda solution of ,35 per cent strength, 800 parts of Water and 300 parts of alcohol for about '3 hours there are then adds;

ed 300 parts of hydrochloric acid 01325 per cent strength, thealcohol is expelled and the" whole is stirred for a iewhoursmi the water bath. On cooling the main quantity of the phthalic acid crystallizes. When it has been separated by filtration the neutralized filtrate can "be evaporated to crystallize the hydro chloride of the 2A- dimethylbenzylamine, hav- 7 ing a melting point of 210 C. and corresponding to the following formula NHz or, by addition of caustic soda to the filtrate, the free base, having a melting point of 218 1 to 219 C., canbe precipitated.

. thylphthalimide is obtained by crystalliza- -3. 195 parts of chloromethylphthalimide and 10 parts of zinc chloride are introduced gradually into 256 parts of molten naphthalene and the whole is heated, while stirring, until evolution of hydrogen chloride has ceased. The unalterednaphthalene is now expelled with steam and the 'l-naphthylmetion from alcohol in form of white crystals and melting at 175 C. 72 parts of this naphthylmethylphthalimide are stirred with 70 parts of caustic soda solution of '35 per cent strength, 200'parts of water and 250 parts 5 of alcohol until complete dissolution. There are then. added 180 parts ofhydrochloric acid of 25 per cent strength, the alcohol is expelled and the residue is stirred while hot until a clear solution is obtained. 7 After coolingexcessf-of strong caustic soda solution is added and -the 1-naphthylmethyla 'nine havingthefollowing formula p onz nrn I is extracted with ether and purified by'distilv lation in a vacuum. I

4. 155- parts of phenol and 325 parts of chloromethylphthalimide are dissolved r in 2500 parts of benzene. After additionof- 7 pure white crystals. 5 5

parts of zinc chloride the mixture is heated gradually on'the water bath to to C.

until evolution of hydrogen chloridehas. ceased. The liquid is decanted and distilled to remove the benzene; 1* rom the residue the condensation product may be obtained by recrystallization from hot alcohol in the form of 25 parts thereof are stirred in the .cold for two hours with 30 parts of'caustic soda solution of 35 per cent strength and 200 parts of water; After'this the whole is acidified with dilute hydrochloric acid and heated on the water bath until some separated oil has passed into solution. By several extractions with ether the: phthalic acid is separated and then the aqueous solution, feebly acid with hydrochloric acid, is

evaporated to dryness in a vacuum; The residue is extracted with anhydrous alcohol. By

' melts at 107 ing the following formula:

- is obtained by evaporating the solution i-hydroxybenzylamine hydrochloride is obtained besides a little 2-hydroxybenzylamine hydrochloride. t hydroxybenzylamine having the following formula:

HOGH2NH1 V C., 2-hydroxybenz'ylamine hav- OH I melts at 129C. f v' 5. 195 parts of 'chloromethylphthalimide are dissolved in 32tparts of methoxybenzene, 10 parts of zinc chloride are added and the When evolution of hydrogen chloride has ceased, the excess of:

whole heated to 120 C.

methoxybenzene is distilled with steam and the residue treated with cold" alcohol, whereby the 4-1nethoxybenzylphthalimide is obtained in nearly theoretical yield in the form of crys-= tals having a melting point of 104 C. 50

parts of this compound are stirred in the cold for 2 hours with 50 parts of alcohol, 100 parts of caustic soda solution of 35 per cent strength and 200 parts of water. The mixture is aciditied with dilute hydrochloric acid, the alcohol expelled and some oil which has separated brought into solution by addition of water. After extracting the phthalic acid with ether, the hydrochloric acid solution is evaporated in avacuum-and the residue is extracted with alcohol to obtain t-methoxy-l-benzylamine hydrochloride. From the concentrated aqueous solution of the salt the the following formula:

H ODOOHrNHz adding caustic soda tracting with ether. V o V 6. 63 parts of guaiacol and 82 parts of chloromethylphthalimide are condensed in the manner prescribed in example 5 but withfree base having and 'ex-.

out the use of a catalyst to form 4-hydroxy-3- methoXybenzylphthalimide of melting point 154 C. By decomposing this product in the manner prescribed vanillylamine (t-hydroxy-3-methoxybenzylamine) having the following formula:

noO-on -Nn stirring, at to. 130 C. until evolution of hydrogen chloride ceases. The excess of nitromethylbenzene is'expelled with steamand the residue is crystallized fro'malcohol'. 100 parts of this condensationfprodu'ct are stirred the water bath until the whole has dissolved.

Aftercooling the separated phthalic acid is filtered and the filtrate'is mixed with excess of ammonia and extracted'with ether which takes out the 3-nitro-l-methyl benzylamine having the following formula:

HaCQ CHr-NHz l OzN i i this may be purified by distillation in a vacuum. r

' 8. 26.5 parts of 2.4-dimethylbenzylphthalimide (compare Example 2) are dissolved in 130-parts of nitrobenzene and the solution is heated with 19.5 parts of chloroinethylphthalimide and 3 parts of zinc chloride atto 100 C. When-evolution of hydrogen chloride is at an end the product crystallizes. it is 2. l-di1nethyl-L5-(omega-phthalimidemethyl) -benzene' and forms white crystals having a melting point of 274 C. After expelling the nitrobenzenea further quantity of the product can be obtained fromthe residue. while heating with 150 parts of alcohol, 150

parts of water and 20 parts ofcaustic soda solution of 35 percent strength until the whole is passed into solution. After cooling there are added parts of hydrochloric acid.

of12 Baumand the mixture is stirred while heating and at the same time expelling alcohol until a clear solution is obtained. From this solution phthalic acid'crystallizes on cooling; the filtrate from this is mixed with excess of caustic soda and extracted with ether. From the ethereal solution there is obtained 2/l-dimethyl-L5-di-(omega-aminomethyl) -benzene having the following formuin the form of white crystals melting at 123 C.

9. 57.4 parts of l-naphthymethylphthali-,

r to 120 C. When evolution of hydrogen chloride is at an end the nitrobenzene is dis-V tilled with steam. The tri-phthalimide thus obtained and derived from 1.4.8tri-(omega- 'aminomethyl) -naphthalene'is in the form of crystals which dissolve with great difficulty in alcohol. 106 parts of this phthalimide are 37 parts of the product are stirred dissolved in'500 partsof alcohol, "4'30fparts of water and 7 0 parts of caustic soda solution" of 85 percent strength, and is then splitup:

by heating the solution with 200 parts ofhydrochloric acid of 12 'Baum. Thephthalicacid is separated, excess of caustic soda-isadd ed'to the solution, which is then extraetedi,

with chloroform. On evaporating the chloroform 1.4.8-tri- (omega-aminomethyl) na-ph' thalene having the following formula: w 1

p 7 VNH 2 U i i remains as an oil soluble in Water and boiling; at240=245 C. at 15 millimeters pressure,

10. 89 parts of anthracene are dissolved together with 195 parts of chloromethylphthalimide and 10 parts of zinc chloride'in nitrobenzene and the soluticnis heatedto 85 to O 146 parts of the product thus obtained are dissolved with aid of heat in 1000 shaken with benzeneto extract the 9.10-di-f (omega -"aminomethyl)- anthracene" having the following formula: 5 N

It forms crystals which are sparingly samba V in water and decomposebetween 250 and 270C.

Inan analogous mannerother carbo cyclic compounds may be condensed with a' lialo genomethylphthalimide, for instance aromat its ic hydrocarbons, hydroaromatic hydrocar atives of such hydrocarbons, ",carboxylic. acids, such as salicyclic acid, arylorn'ethyL 'phthalimides and generally carbo cyclic}com pounds: containing radicals of an acid character. l

Vllhat we claim is i 1. The process which comprises heating boils such as y hexane and tetraliydro n lene, halogen derivatives,fnitro del'lvatives, y r xy derivatives, ,alkoXy d -iv r about 63:,parts of guaiacol and'32 N (chloro-methyl) -phthalimide tjof fteih? pe'rature of about C. until evolutioii or we I hydrogen chloride has ceased, isolating the i-hydrOxy-S-m e t h X y-benzyl-phthalimide thus obtained, splitting it in the .cold with a caustic soda solution, and in succession splitsubstituted in the alkyl group by an aromatic compound, the step which comprises condensing an N (halogen-methyl) -phthalimide with an aromatic compound, havinga labile hydrogenatom attached to a cyclic --carbon atom..

4. In the manufacture of alkylamines substituted in the alkyl group byan aromatic compound, the step which comprises condensing N-(chloro-methyl)-phthalimide with an aromatic compound, having a labile hydrogen atom attached to, a cyclic carbon atom.

- 5.- In the-manufacture of alkylamines substituted in the alkyl group .by an aromatic compound, the step which comprises con- .densing N- (chloro-methyl) -phthalimide with an aromatic compound being substituted by at leastonesubstituent of the group consist ing of hydroxyl and alkoxyl, but havinga labile hydrogen atom attached toa cyclic carbon atom. o 6. In the manufacture of alkylamines substituted in the alkyl group by an aromatic compound, the step whichcomprises condens-.

' ing N-(chlorounethy'l) -phthalimide with an alkoXy-aryl compound, having a labile hydrogenatom attached" to" acyclic carbon atom. v

7.'In the manufacture of vanillylamine the step which comprises condensing N- (chloro-methyl) -phthalimide with guaiacol.

8. The process which comprises condensing an N- halogen-methyl) -phthalimide with 1 a carbocyclic compound having a labile hydrogen atom attached to acyclic carbon atom,

splitting thecondensation product formed with an alkali and in successionsplitting the N-substituted phthalamic acid formed with an amount of diluted acid approximately required to neutralize the alkali added and to bind the finally formed methylamines aromatically substituted in the methyl group.

9. The process which comprises condensihg'an' N- (halogen-methyl) -phthalimidew ith an aromatic compound having .a labile hydrogen atom attached to a cycliccarbon atom, splitting the condensation product formed with an alkali and-in succession splitting the ltl slibstitutedl hthalamic acid formedlwith I an amount of diluted acid approximately required to neutralize the alkali addedand to bind the finallyformed methylamines aromatically substituted in the methyl group.

'10, The. process which comprises condensing N (chloro-methyl) t-phthali'mide with an aromatic compound having a labile hydrogen atom attached to a cyclic carbon atom, splitting the condensation product formed with an alkali. and in succession splitting the N- substituted phthalamic acid formed with an.

amount of diluted acid approximately rel quired to neutralize the alkali added and to bind the finally formed methylamines aromatically substituted in the methyl group.

11. The process which comprisescondensing N- (ochloro-methyl) -phthalimide with an aromatic compound having a labile hydrogen atomattached to a cyclic carbon atom, but bein substituted by-at least one'substituent of t e group consisting of liydroxyl and s alkoxy, splitting the condensation product formed with an alkali and in succession splitting the N-substituted; phthalamic acid formed with an amount of diluted acid approximately required to. neutralize the alkali added and to bind the finally formed methylamines aromatically substituted 'in the methyl-group. r o

12. The process which comprises condensing an 'N-(chloro-methyl) -phthalimide with an alkoxy-aryl compound having a labile hy-' drogen atom-attached to a cyclic carbon atom, splitting the condensation product formed with an alkali andfin'succession splitting the N-substituted phthalamic acid formed with an amount of diluted acid approximately required to neutralize the-alkali added and to bind the finally formedlmethylamines are?- I maticallylsubstituted in the. methyl group.

13. The process which comprises condenslng N-(chloro-methyl) -phthalimidej I with guaiacol, splitting the condensation product formedwith'an' alkali and in succession splittlng the 14-hydroxy-3-methoxybenzylphthalamic acid with an amount of diluted acid approximately required to neutralize the alkali added and to bind the vanillylamine formed. In testimony whereof we aflix our signa tures.

WILHELM 'HERZBERG. HANS LANGE. 

